From 2646 to 15: differentially regulated microRNAs between progenitors from normal myometrium and leiomyoma.

BACKGROUND: Uterine leiomyomas (fibroids) are smooth muscle neoplasms of the myometrial layer of the uterus and are the most common benign tumors in women. Although their etiology is still unclear, progenitor cells seem to be implicated. OBJECTIVE: To identify the dysregulated pathways involved in leiomyoma onset by microRNA profiling of progenitor cells isolated from normal myometrium and leiomyoma tissue. MATERIALS AND METHODS: Pairs of normal myometrium and uterine fibroid specimens were collected from 12 myomectomy patients. Myometrial progenitor cells and leiomyoma progenitor cells were isolated and characterized for stemness. After total RNA extraction and profiling of their 2646 microRNAs, DIANA-miRPath analysis was applied to find any dysregulated pathways. RESULTS: Only 30 microRNAs showed a significant differential regulation between myometrial progenitor cells and leiomyoma progenitor cells. Removal of those that had values close to the cut-off or that were not consistent among triplicates left 15 microRNAs, of which 7 were downregulated and 8 were upregulated in leiomyoma progenitor cells compared to myometrial progenitor cells. According to DIANA-miRPath analysis, the 7 downregulated microRNAs (hsa-miR-146b-5p; hsa-miR-335-3p; hsa-miR-335-5p; hsa-miR-135b-5p; hsa-miR-10a-3p; hsa-miR-10a-5p; hsa-miR-200a-3p) are all related to 3 pathways, "ECM-receptor interaction" (33 targeted genes), "Adherens junction" (33 targeted genes), and "Hippo signaling" (69 targeted genes), whereas the 8 upregulated miRNAs (hsa-miR-146a-5p; hsa-miR-576-3p; hsa-miR-122-5p; hsa-miR-1246; hsa-miR-595; hsa-miR-658; hsa-miR-4284; hsa-miR-924) are related to 4 pathways, "PI3K-Akt signaling pathway" (71 targeted genes), "Pathways in Cancer" (80 targeted genes), "Cell Cycle" (37 targeted genes), and "Regulation of actin cytoskeleton" (41 targeted genes). CONCLUSION: The findings that only 15 of 2646 microRNAs are differentially regulated in normal myometrium and leiomyoma and that they are involved in 7 dysregulated pathways provides interesting insights into the development of uterine fibroids, and lends support to the hypothesis that leiomyoma onset is the result of alterations affecting progenitor cells.

The senescent status of endothelial cells affects proliferation, inflammatory profile and SOX2 expression in bone marrow-derived mesenchymal stem cells.

Human aging is a physiological process characterized by a chronic low-grade inflammation. Senescence may affect endothelial cells, subsequently involved in the most common age-related diseases (ARDs), as well as mesenchymal stem cells (MSCs) with an impairment of their properties in tissues regeneration. Endothelial cells seem to be able to exert a paracrine effect on BM-MSCs through the secretion of pro-inflammatory factors. This work is aimed to evaluate if the senescent status of human umbilical vein endothelial cells (HUVECs) could affect bone marrow derived MSCs (BM-MSCs) proliferative ability and stemness. HUVECs were cultured until the senescence status. Young (passage 3) and senescent HUVECs (passage 13) were indirectly co-cultured with BM-MSCs for 8 days in order to evaluate the effect of their senescence status on proliferative ability and stemness of MSCs. The co-culture of senescent HUVECs with BM-MSCs was associated with a reduced proliferative ability of BM-MSCs, an enforced pro-inflammatory phenotype of BM-MSCs (increased synthesis of proinflammatory cytokines such as IL-6 and TNF-α) and an increased expression of miR-126a-3p, in association with a significant decrease of SOX2, a stemmness- associated gene, targeted by miR-126a-3p. A more general IPA analysis, revealed as miR-126a-3p also modulates the expression of IRS1, IRS2, IL6ST and PIK3R2, all targets that enforce the hypothesis that senescent endothelial cells may reduce the proliferative ability and the stemness phenotype of bone marrow-derived mesenchymal stem cells.

Mesenchymal Stem Cells from Nucleus Pulposus and Neural Differentiation Potential: a Continuous Challenge.

Mesenchymal stem cells (MSCs) are well-characterized adult stem cells, recently isolated from human nucleus pulposus of degenerate and non-degenerate intervertebral disc. The attention to this source is linked to its embryologic history and cells may conserve a stronger aptitude to neuronal differentiation than other MSCs. Here, MSCs from nucleus pulposus (NP-MSCs) were successfully isolated and characterized for morphology, proliferation, and expression of selected genes. Subsequently, the neuronal differentiation was induced by 10 days of culture with a neuronal medium. NP-MSCs subjected to neural differentiation media (NP-MSCs-N) showed a morphological and biochemical modifications. NP-MSCs-N displayed elongated shape with protrusion, intermediate filaments, microtubules, and electron dense granules and the ability to form neurospheres. Even if they expressed neural markers such as NESTIN, ß-TUBULIN III, MAP-2, GAP-43, and ENOLASE-2, the neural differentiated cells did not show neither spontaneous nor evoked intracellular calcium variations compared to the undifferentiated cells, suggesting that cells do not have electric functional properties. Further studies are required in order to get a better understanding and characterization of NP-MSCs and analyzed the molecular mechanisms that regulate their neural differentiation potential.

Breast Implant Texturization Does Not Affect the Crosstalk Between MSC and ALCL Cells.

In the last decade, there has been a growing interest about the possible association between anaplastic large cell lymphoma (ALCL) and breast implants (BIA-ALCL). Many variables, such as breast implants texturization, have been investigated. Breast implants often lead to the formation of a periprosthetic capsule, characterized by inflammation. The presence of the inflamed capsule has been found in the majority of patients with BIA-ALCL. Inflammation may be sustained or counteracted by mesenchymal stem cells (MSCs) by the secretion of pro- or anti-inflammatory cytokines. MSCs were isolated from three capsules surrounding micro-textured (micro-MSCs) and from three capsules surrounding macro-textured (macro-MSCs) implants; after characterization, MSCs were co-cultured with KI-JK cells (a cell line derived from the cutaneous form of ALCL). The secretion of cytokines related to inflammation, the proliferation rate, and the expression of genes referred to pro-tumoral mechanisms were evaluated. Co-cultures of KI-JK cells with micro- or macro-MSCs gave the same results about the secretion of cytokines (increase of IL10, G-CSF, and TGF-ß1 and decrease of IL4, IL5, IL12, IL13, IL17A, IFN-γ (p < 0.05) with respect to mock sample), expression of selected genes (increase for ACVR1, VEGF, TGF-ßR2, CXCL12, and MKi67 (p < 0.05) with respect to control sample), and the proliferation rate (no variation between mock and co-cultured samples). Our results suggest that MSCs derived from capsules surrounding micro- and macro-textured implants display the same effects on the ALCL cells.

Prognostic implication of CEACAM1 expression in squamous cell carcinoma of the larynx: Pilot study.

BACKGROUND: CEACAM1, a valuable biomarker for several cancers, have remained unexplored up to the present in laryngeal squamous cell carcinoma (LSCC). We aimed to examine CEACAM1 expression and evaluate its combinational clinical significance for the diagnosis or prognosis and treatment decision making in LSCC. METHODS: CEACAM1 expression was assessed by immunohistochemistry in 54 LSCCs and evaluate its correlation with clinical and histopathological features. RESULTS: CEACAM subtype 1 (CEACAM1) expression was positive in 50% of the cases. No significant difference was observed in relation to age, gender, tumor size, and tumor stage. CEACAM1 expression correlated with tumor grade, development of local recurrence, node and distant metastasis. Kaplan-Meier survival curves showed that CEACAM1 staining was inversely correlated with both overall and disease-specific 5-year survival. CONCLUSIONS: Our study is the first to demonstrate that CEACAM1 expression is associated with an adverse prognosis in LSCC. CEACAM1 is a valuable biomarker and a promising therapeutic target in LSCC.

Effects of senescent secretory phenotype acquisition on human retinal pigment epithelial stem cells.

Regenerative medicine approaches based on mesenchymal stem cells (MSCs) are being investigated to treat several aging-associated diseases, including age-related macular degeneration (AMD). Loss of retinal pigment epithelium (RPE) cells occurs early in AMD, and their transplant has the potential to slow disease progression.The human RPE contains a subpopulation of cells - adult RPE stem cells (RPESCs) - that are capable of self-renewal and of differentiating into RPE cells in vitro. However, age-related MSC changes involve loss of function and acquisition of a senescence-associated secretory phenotype (SASP), which can contribute to the maintenance of a chronic state of low-grade inflammation in tissues and organs.In a previous study we isolated, characterized, and differentiated RPESCs. Here, we induced replicative senescence in RPESCs and tested their acquisition of the senescence phenotype and the SASP as well as the differentiation ability of young and senescent RPESCs.Senescent RPESCs showed a significantly reduced proliferation ability, high senescence-associated ß-galactosidase activity, and SASP acquisition. RPE-specific genes were downregulated and p21 and p53 protein expression was upregulated.These findings document the effects of senescence and SASP acquisition on RPESC differentiation ability and highlight the need for a greater understanding of their role in AMD pathogenesis.

Pathogenetic Characteristics of Mesenchymal Stem Cells in Hidradenitis Suppurativa.

Importance: Hidradenitis suppurativa (HS) is a disease of the terminal hair follicle in apocrine gland-enriched skin areas, where immunobiology dysregulation of mesenchymal stem cells (MSCs) may have a key role. Objective: To investigate the MSC profile in patients with HS and in healthy controls. Design, Setting, and Participants: In this prospective case-control study, patients with HS were recruited from the Dermatological Clinic at the Department of Clinical and Molecular Sciences, Università Politecnica delle Marche, Ancona, Italy. Biopsy specimens were analyzed at the Histology Section of the Department of Clinical and Molecular Sciences. Participants included 11 patients with HS and 9 healthy controls, who were recruited into the study between January 20, 2015, and September 20, 2016, and underwent punch biopsy from axillary skin. None of the participants had received any antibiotics (systemic or topical therapy) within almost 12 weeks before the study. Main Outcomes and Measures: The immunophenotypic profile of MSCs was characterized following the minimal criteria established by the International Society for Cellular Therapy for the identification of MSCs. Levels of 12 cytokines belonging to helper T-cell subtypes 1, 2, and 17 pathways were examined on the secretome of isolated cells by enzyme-linked immunoabsorbent assay. Results: Skin MSCs were characterized in 11 patients with HS (8 women and 3 men; mean [SD] age, 35.8 [7.9] years) and 9 healthy controls (7 women and 2 men; mean [SD] age, 36.7 [6.9] years). The healthy controls were matched with patients with HS for body mass index. Mesenchymal stem cells isolated from patients with HS (HS-MSCs) and from healthy controls (C-MSCs) met the International Society for Cellular Therapy minimal criteria. Compared with C-MSCs, cytokine analyses of HS-MSCs revealed statistically significant overexpression of interleukin (IL) 6 (median [interquartile range {IQR}], 8765.00 [7659.00-9123.00] vs 2849.00 [2609.00-3001.00] pg/mL; P = .008), IL-10 (median [IQR], 29.46 [26.35-35.79] vs 21.36 [19.89-23.33] pg/mL; P = .004), IL-12 (median [IQR], 15.25 [13.27-16.25] vs 11.89 [10.73-12.33] pg/mL; P = .03), IL-17A (median [IQR], 15.24 [13.23-17.24] vs 11.24 [10.28-11.95] pg/mL; P = .008), tumor necrosis factor (median [IQR], 42.54 [42.20-43.94] vs 32.55 [31.78-33.28] pg/mL; P = .004), transforming growth factor ß1 (median [IQR], 1728.00 [1535.00-1979.00] vs 500.80 [465.00-634.50] pg/mL; P = .004), and interferon γ (median [IQR], 11.49 [10.71-12.35] vs 9.45 [9.29-10.01] pg/mL; P = .005). Conclusions and Relevance: Mesenchymal stem cells isolated from the skin of patients with HS seem to be activated toward an inflammatory status. The imbalance between proinflammatory and anti-inflammatory activities of MSCs favors the hypothesis of their pathogenic involvement in HS.

Chronic Inflammation May Enhance Leiomyoma Development by the Involvement of Progenitor Cells.

Although the etiology of leiomyoma is unclear, a progenitor/undifferentiated cell population has been described whose dysregulation may be involved in the onset of uterine conditions. Moreover, inflammation is involved in the development of several tumors. The aim of this work was to understand if progenitor cells sustain a chronic inflammatory microenvironment that enhances leiomyoma development. Cells from 12 human leiomyoma and 12 normal myometrium samples of the same patients were in vitro isolated and exhaustively characterized (morphology, proliferation, cytofluorometry, differentiation, RT-PCR, immunofluorescence, immunohistochemistry, and Western blotting assays). Selected cytokines (ELISA) and inflammation-related genes (RT-PCR) were analyzed to identify healthy myometrium progenitor cells (MPCs) and leiomyoma progenitor cells (LPCs). Results show that (i) MPCs and LPCs share stemness features, such as immunophenotype and multidifferentiation assay, (ii) LPCs have a significantly shorter doubling time and a significantly higher expression of stemness genes (p < 0.05), and (iii) LPCs secreted significantly higher levels (p < 0.05) of cytokines related to chronic inflammation and significantly lower amounts (p < 0.05) of cytokines related to acute inflammation. Despite the limited sample size, comparisons between leiomyoma and normal myometrium tissue from each patient allowed normalization of patient-specific differences. The evidenced cytokine expression pattern related to chronic inflammation in LPCs may play a role in the increased risk of adverse obstetric outcomes (infertility, spontaneous miscarriage, and preterm birth) in women affected by leiomyomas. These women should be recognized as "high risk" and subjected to specialized management both before and during pregnancy.

Allyl Isothiocyanate Exhibits No Anticancer Activity in MDA-MB-231 Breast Cancer Cells.

It was reported recently that allyl isothiocyanate (AITC) could inhibit various types of cancer cell growth. In the present study, we further investigated whether AITC could inhibit the growth of human breast cancer cells. Unexpectedly, we found that AITC did not inhibit, rather slightly promoted, the proliferation of MDA-MB-231 breast cancer cells, although it did have inhibitory effect on MCF-7 breast cancer cells. Cytofluorimetric analysis revealed that AITC (10 µM) did not induce apoptosis and cell cycle arrest in MDA-MB-231 cells. In addition, AITC significantly (p < 0.05) increased the expression of BCL-2 and mTOR genes and Beclin-1 protein in MDA-MB-231 cells. No significant changes in expression of PRKAA1 and PER2 genes, Caspase-8, Caspase-9, PARP, p-mTOR, and NF-κB p65 proteins were observed in these AITC-treated cells. Importantly, AITC displayed cytotoxic effect on MCF-10A human breast epithelial cell line. These observations suggest that AITC may not have inhibitory activity in MDA-MB-231 breast cancer cells. This in vitro study warrants more preclinical and clinical studies on the beneficial and harmful effects of AITC in healthy and cancer cells.

Correlation between immunohistochemical staining of CEACAM1 and clinicopathological findings in oral pre-neoplastic lesions and squamous cell carcinoma.

Squamous cell carcinoma of the oral cavity represents the sixth most common cancer worldwide and it is often preceded by pre-neoplastic lesions. Sometimes it is still difficult for pathologists to make objective differential diagnoses only on histological characteristics. Tumorigenesis is accompanied by altered expression of cell adhesion molecules, like carcinoembryonic antigen cell adhesion molecule (CEACAM)1. We wanted to investigative CEACAM1 in oral dysplastic lesions, carcinoma in situ (CIS) and oral squamous cell carcinoma (OSCC). We examined immunohistochemical CEACAM1 expression in 50 OSCC, 30 oral CIS and 40 pre-neoplastic lesions and assessed its correlation with clinical and pathological parameters. CEACAM1 was not expressed in normal mucosa, significantly expressed in CIS while it was negative in all the dysplastic lesions. In OSCC, high CEACAM1 expression was associated with tumor grade and inversely correlated with both overall and disease-specific 5-year survival. We showed that CEACAM1 expression is very dynamic: absent in dysplastic lesions, up-regulated in CIS and OSCC. We suggest that CEACAM1 could be a prognostic marker of OSCC and oral CIS. Our most important finding was that it could help pathologists diagnosing oral carcinoma in situ.

Mesenchymal Stem Cells from Cervix and Age: New Insights into CIN Regression Rate.

Cervical intraepithelial neoplasia (CIN) is a precancerous lesion of the uterine cervix that can regress or progress to cervical cancer; interestingly, it has been noted that young women generally seem to have higher rates of spontaneous regression and remission, suggesting a correlation between the patient's age and regression/progression rates of CIN. Even if the underlying mechanisms are still unclear, inflammation seems to play a pivotal role in CIN fate and inflammatory processes are often driven by mesenchymal stem cells (MSCs). This study was aimed at evaluating if age affects the behavior of MSCs from the cervix (C-MSCs) that in turn may modulate inflammation and, finally, regression rate. Fourteen samples of the human cervix were recovered from two groups of patients, "young" (mean age 28 ± 2) and "old" (mean age 45 ± 3), during treatment using the loop electrosurgical excision procedure (LEEP) technique. Progenitor cells were isolated, deeply characterized, and divided into young (yC-MSCs) and old cervixes (oC-MSCs); the senescence, expression/secretion of selected cytokines related to inflammation, and the effects of indirect cocultures with HeLa cells were analyzed. Our results show that isolated cells satisfy the fixed criteria for stemness and display age-related properties; yC-MSCs express a higher level of cytokines related to acute inflammation than oC-MSCs. Finally, in the crosstalk with HeLa cells, MSCs derived from the cervixes of young patients play a stronger antitumoral role than oC-MSCs. In conclusion, the immunobiology of MSCs derived from the cervix is affected by the age of donors and this can correlate with the regression rate of CIN by influencing their paracrine effect. In addition, MSCs from a young cervix drives an antitumoral effect by sustaining an acute inflammatory environment.

Increase of n-NOS and i-NOS in Rat Colon After Sacral Neuromodulation.

OBJECTIVE: Sacral neuromodulation (SNM) is proposed to treat different anorectal dysfunctions but its mechanism of action is not yet known. Our previous study demonstrated how SNM can significantly increase neuronal nitric oxide synthase NOS (n-NOS) and inducible NOS (i-NOS) expression in the anus and rectum of rats. There are no reports regarding the relation between SNM and NOS in colonic cells: our aim was to assess NOS expression in colonic rat model after SNM. MATERIALS AND METHODS: Twenty-six female Sprangue-Dawley rats were considered: group I, normal control rats; group II, sham treatment rats, in whom electrodes for electrical stimulation were placed in S1 foramen bilaterally and left in place, without performing neuromodulation; group III, rats in whom SNM was performed. After 14 days, the rats were sacrificed and we evaluated n-NOS and i-NOS in colonic specimens by immunohistochemistry and Western Blot analysis. RESULTS: Western Blot analysis showed that levels of n-NOS and i-NOS were higher in colon of the III group rats respect to the others; in particular, immunohistochemistry revealed that, after neuromodulation, n-NOS expression in the muscle cells and i-NOS expression in glandular epithelium and nervous cells were highly represented (p < 0.05). CONCLUSION: Our study showed that in colon, SNM is able to influence NO synthesis, activating n-NOS expression in muscle cells and i-NOS expression in glandular epithelium and nervous cells. Our study showed a complex colonic response to SNM. This experimental model could be applied to better understand the mechanism of action of SNM in bowel dysfunction.

Regulation of microRNA using promising dietary phytochemicals: Possible preventive and treatment option of malignant mesothelioma.

Malignant mesothelioma (MM) is a very aggressive, lethal cancer, and its incidence is increasing worldwide. Development of multi-drug resistance, therapy related side-effects, and disease recurrence after therapy are the major problems for the successful treatment of MM. Emerging evidence indicates that dietary phytochemicals can exert anti-cancer activities by regulating microRNA expression. Until now, only one dietary phytochemical (ursolic acid) has been reported to have MM microRNA regulatory ability. A large number of dietary phytochemicals still remain to be tested. In this paper, we have introduced some dietary phytochemicals (curcumin, epigallocatechin gallate, quercetin, genistein, pterostilbene, resveratrol, capsaicin, ellagic acid, benzyl isothiocyanate, phenethyl isothiocyanate, sulforaphane, indole-3-carbinol, 3,3'-diindolylmethane, diallyl disulphide, betulinic acid, and oleanolic acid) which have shown microRNA regulatory activities in various cancers and could regulate MM microRNAs. In addition to microRNA regulatory activities, curcumin, epigallocatechin gallate, quercetin, genistein, resveratrol, phenethyl isothiocyanate, and sulforaphane have anti-mesothelioma potentials, and pterostilbene, capsaicin, ellagic acid, benzyl isothiocyanate, indole-3-carbinol, 3,3'-diindolylmethane, diallyl disulphide, betulinic acid, and oleanolic acid have potentials to inhibit cancer by regulating the expression of various genes which are also known to be aberrant in MM.

Role of Daptomycin on Burn Wound Healing in an Animal Methicillin-Resistant Staphylococcus aureus Infection Model.

Prolonged hospitalization and antibiotic therapy are risk factors for the development of methicillin-resistant Staphylococcus aureus (MRSA) infections in thermal burn patients. We used a rat model to study the in vivo efficacy of daptomycin in the treatment of burn wound infections by S. aureus, and we evaluated the wound healing process through morphological and immunohistochemical analysis. A copper bar heated in boiling water was applied on a paraspinal site of each rat, resulting in two full-thickness burns. A small gauze was placed over each burn and inoculated with 5 × 107 CFU of S. aureus ATCC 43300. The study included two uninfected control groups with and without daptomycin treatment, an infected control group that did not receive any treatment, and two infected groups treated, respectively, with intraperitoneal daptomycin and teicoplanin. The main outcome measures were quantitative culture, histological evaluation of tissue repair, and immunohistochemical expression of wound healing markers: epidermal growth factor receptor (EGFR) and fibroblast growth factor 2 (FGF-2). The highest inhibition of infection was achieved in the group that received daptomycin, which reduced the bacterial load from 107 CFU/ml to about 103 CFU/g (P < 0.01). The groups treated with daptomycin showed better overall healing with epithelialization and significantly higher collagen scores than the other groups, and these findings were also confirmed by immunohistochemical data. In conclusion, our results support the hypothesis that daptomycin is an important modulator of wound repair by possibly reducing hypertrophic burn scar formation.

Prognostic role of BAP1 in pT1 clear cell carcinoma in partial nephrectomy specimens.

BAP1 is a gene situated on chromosome 3p in a region that can be modified in renal cell carcinomas (RCCs). Mutations that cause loss of expression of BAP1 frequently occur in primary clear cell renal carcinoma (ccRCC). In a previous work, we observed that loss of nuclear BAP1 expression was crucial in ccRCC progression; in the current study, we investigated BAP1 expression in a large series of small conventional ccRCCs treated with partial nephrectomy, to assess a possible role as biomarker and the prognostic value in terms of patients' survival at long-term follow-up. One hundred sixty-two patients with single pT1 ccRCC were selected from those who underwent surgery at our Institute of Urology between 1987 and 2000. The features considered in this study were gender, age, tumor size, grade, incidence of metastasis, and patient-specific survival; they were correlated with immunohistochemical BAP1 nuclear expression in tumoral tissue. Median follow-up was 197.24 months (range 19 to 274); median survival was 125.34 months (range 5 to 274 months). None of our pT1 ccRCCs showed total loss of nuclear BAP1 staining; we found a significant negative correlation between nuclear BAP1 expression and tumor size and between nuclear BAP1 expression and grade. In small ccRCCs, nuclear BAP1 staining was not correlated with disease-specific 5-year survival.Our data confirm the established role of BAP1 as a tumor suppressor protein. This is the first report where BAP1 has been studied in pT1 ccRCC tumors, but nuclear BAP1 expression cannot help identify patients having high-risk disease in these patients.

Biofabrication and Bone Tissue Regeneration: Cell Source, Approaches, and Challenges.

The growing occurrence of bone disorders and the increase in aging population have resulted in the need for more effective therapies to meet this request. Bone tissue engineering strategies, by combining biomaterials, cells, and signaling factors, are seen as alternatives to conventional bone grafts for repairing or rebuilding bone defects. Indeed, skeletal tissue engineering has not yet achieved full translation into clinical practice because of several challenges. Bone biofabrication by additive manufacturing techniques may represent a possible solution, with its intrinsic capability for accuracy, reproducibility, and customization of scaffolds as well as cell and signaling molecule delivery. This review examines the existing research in bone biofabrication and the appropriate cells and factors selection for successful bone regeneration as well as limitations affecting these approaches. Challenges that need to be tackled with the highest priority are the obtainment of appropriate vascularized scaffolds with an accurate spatiotemporal biochemical and mechanical stimuli release, in order to improve osseointegration as well as osteogenesis.

Inflammation by Breast Implants and Adenocarcinoma: Not Always a Bad Company.

BACKGROUND: Inflammation and tumor are now an inseparable binomial. Inflammation may also derive by the use of breast implants followed by the formation of a periprosthetic capsule. It is known that tumor cells, in an inflamed microenvironment, can profit by the paracrine effect exerted also by mesenchymal stem cells (MSCs). Here we evaluated the role of inflammation on the immunobiology of MSCs before and after cocultures with cells derived from breast adenocarcinoma. METHODS: MSCs derived from both inflamed (I-MSCs) and control (C-MSCs) tissues were isolated and cocultured with MCF7 cells derived from breast adenocarcinoma. Before and after cocultures, the proliferation rate of MCF7 cells and the expression/secretion of cytokines related to inflammation were tested. RESULTS: Before cocultures, higher levels of cytokine related to chronic inflammation were detected in I-MSCs than in C-MSCs. After cocultures with MCF7, C- and I-MSCs show a variation in cytokine production. In detail, IL-2, IL-4, IL-5, IL-10, IL-13, TGF-ß and G-CSF were decreased, whereas IL-6, IL-12, IFN-γ, and IL-17 were oversecreted. Proliferation of MCF7 was significantly increased after cocultures with I-MSCs. CONCLUSIONS: Inflammation at the site of origin of MSCs affects their immunobiology. Even if tumor cells increased their proliferation rate after cocultures with I-MSCs, the analysis of the cytokines, known to play a role in the interference of tumor cells with the host immune system, absolves completely the breast implants from the insult to enforce the risk of adenocarcinoma.

TNF-α inhibitors reduce the pathological Th1 -Th17 /Th2 imbalance in cutaneous mesenchymal stem cells of psoriasis patients.

Psoriasis is a disease characterized by an imbalance between Th1 and Th17 and Th2 inflammatory axes, in which cutaneous mesenchymal stem cells (MSCs) are early involved, as they show a greater relative expression of several genes encoding for Th1 and Th17 cytokines. Therapeutic implications of TNF-α inhibitors on differentiated skin cells have been largely described in psoriasis; however, their effects on MSCs derived from patients with psoriasis have been only partially described. The aim of this work was to evaluate the effect of TNF-α inhibitors on cytokine milieu expressed by MSCs isolated from the skin of patients with psoriasis. Resident MSCs from skin of patients with psoriasis and healthy subjects have been isolated, characterized and profiled by PCR and ELISA for the expression of 22 cytokines involved in Th1 , Th2 and Th17 pathways, both before and after 12 weeks therapy with TNF-α inhibitors. The administration of TNF-α inhibitors for 12-weeks acts on MSCs as follows: it reduces the expression of several Th1 -Th17 cytokines whose levels are elevated at baseline (IL-6, IL-8, IL-12, IL-23A, IFN-γ, TNF-α, CCL2, CCL20, CXCL2, CXCL5, IL-17A, IL-17C, IL-17F, IL-21, G-CSF). Similarly, it enhances the expression of several Th2 cytokines which are underexpressed at baseline (IL-2, IL-4, IL-5), reducing the expression of those overexpressed at baseline (TGF-ß and IL-13). TNF-α inhibitors could contribute to reduce the pathological imbalance between the Th1 -Th17 vs Th2 axis in MSCs of patients with psoriasis.

Role of mesenchymal stem cells in the pathogenesis of psoriasis: current perspectives.

Mesenchymal stem cells (MSCs) are multipotent nonhematopoietic stromal cells studied for their properties and importance in management of several skin diseases. This review collects and analyzes the emerging published data, which describe the function of MSCs in the pathogenesis of psoriasis.

Effects of somatostatin and its analogues on progenitor mesenchymal cells isolated from human pituitary adenomas.

PURPOSE: Progenitor mesenchymal cells (PMCs) have been found also in epithelial tumors and may derive from cancer stem cells (CSCs) by EMT mechanism. In this scenario, the effects of traditionally drugs on PMCs become of primary concern for therapeutic approaches. Previously, we isolated PMCs from acromegalic (GHomas) and not-functioning pituitary adenomas (NFPAs). Here we evaluate: (1) the role of EMT on their origin; (2) the presence of the somatostatin receptors (SSTR1-5); (3) the effects of somatostatin (SST) and its analogues (SSAs) on PMCs proliferation, apoptosis and SSTR1-5 expression. METHODS: PMCs were isolated from GHomas and NFPAs; the expression of E-CADHERIN and TGFßRII (referred to EMT), the expression of the SSTR1-5 as well as the proliferation and apoptosis were tested before and after drugs administration. RESULTS: Results show a decrease of E-CADHERIN and an increase of TGFßRII, confirming an EMT involvement; SSTR1-5 are more expressed by PMCs from GHomas than from NFPAs. SST and SSAs administration does not affect cell proliferation and SSTR1-5 expression on PMCs from NFPAs while in PMCs from GHomas, cell proliferation showed a marked decrease and a corresponding increase in the expression of SSTR1-2. Apoptosis rate and EMT were not affected by drugs administration. CONCLUSIONS: Results indicate as EMT may be related to the presence of PMCs on pituitary tumors; SSAs, currently used in the management of human GHomas, exert anti-proliferative effect also in PMCs that, because of their derivation from CSCs, may be a new meaningful target for drugs treatment.